Preparation of quinazolones



Patented Apr. 13,1948 i i it I UNITED STATES PATENT OFFICE] PREPARATION or QUINAZOLONES Alfred Guenther, Riegelsville, Pa., and Jack F.

Morgan, Phillipsburg, N.'J.,- as'signors to General Aniline & Film Corporation, New York, a N.=Y., a corporation of Delaware i No Drawing. Application April 7, 1945,

Serial No. 587,212.

I 11 Claims. ((31.260-251 The present invention relates to the prepararadical such as alkyl as above and alkylamino tion of substituted quinazolones and to such such as methylamino, ethylamino and'the like, quinazolones. an aromatic radical such as phenyl', toluyl, anisyl,

It has been suggested that .quin-azolones. be phenetyl, o-nitrophenyl, m-nitrophenyl, p-nit-roprepared by the interaction of acylanthranils 5 phenyl, p-chlolrophenyl, naphthyl, phenylamino with amines. While this method can be operated and the like, or araliphatic such as benzyl, to give good yields, it nevertheless requires the menaphthyl and the like. Where-Y is alkylamino employment of intermediates. which are highly or phenylamino, the, alkyl or phenyl radical will unstable with respect to moisture. Consequently, be separated from the quinazolone nitrogenby considerable care must be exercised in the han- '10 an NH- group,,wh ereas when R. is aralkyl, the dling of the intermediates if satisfactory yields aryl radical thereof will be separated from the are to be obtained. quinazolone nitrogen by a -CH2, group. The- Most of the other methods which have been aromatic or heterocyclic nucleus represented by employed for the, production. of quinazolones rethe character R may be benzene, naphthalene, quire. the use of. such high temperatures asneces- 1 5 anthracene, anthraquinone dibenzofurane, carsarily cause some decomposition of the reactants. bazole, diphenylene sulfide and the like.

For example, 2-methyl-3-phenyl-4-quinazolone The reaction may be carried out, by heating has been prepared by heating o-acetamido-benzthe N-acyl-o-amino-cyolic carboxylic acid with anilide to temperaturesofj175. to 210 C. These the primary amine in a suitable solvent in the procedures suffer from the disadvantages that presence of phosphorus trichloride or phosphorus the decomposition involved not only lowers the oxychloride. The phosphorus chloride, preferyield but through lay-product formation decreases ably diluted with a small amount of the solvent the purity of the desired end product. employed, is added slowly and por-tionwise to the It has now been discovered that substituted solution of the other components. The degree of quinazolones can be prepared while avoiding the heating to effect the reaction will dependon the: disadvantages of the prior art methods by the nature of the reactants. Preferably, the-temperneaction of common stable starting materials. ature is one at which the reaction mixture re- The common stable starting materials are N-acylfluxes, although lower temperatures. may be emo-amino cyclic carboxylic acids, primary amines, ployed.

andphosphorus. trichlorideor phosphorus oxy- The N-acyl amino cyclic carboxylic acids -em-- chloride. These productsreact together smoothly ployed may be represented by the following forat moderately elevated temperatures. to produce mula: Y. the desired quinazolones in a pure condition and H in good yields. The preparation of the. quin- NC oz azolones while employing these starting materials e and the quinazolones so obtained accordingly 7 constitute the purposes and objects of the present COOH invention. 1

l lin which 2 is alkyl such as methyl, ethyl, propyl, The quinazolones' the production of *WhdOh is I l 1 contemplated herein have the following struc- 40 butyl octyl decyl andthe and R has the values given above, the amide group and the formula" carboxylic acid group being in o-pcsition of the nucleus represented by R. Examples of such (J-X v compounds are:

\ N-acetyli anthranilic acid N-acetyl-B-chloro anthranilic acid.- II. N -propiony1' anthranilic acid 0 N-butyryl anthranilic, acid in which R is an aromatic or heterocyclic nucleus naphtholc acid which may be substituted by monovalent groups, 0 fiifizz i:gjfizig i gggggfi i g for example, nitro, halogen, such as chlorine, cety1 5 eth0x anthmnflic acid bromine and'the like, alkyl such. as methyl, ethyl, y y

propyl, but'yl, amyl', l'auryl' stearyl and the like, and the like.

akoxy such as. methoxy, ethoxy, propoxy and the The amines which are to be reacted with the like, X is alkyl" as above and Y is an aliphatic acylamino carboxylic acids must contain a pri-- the amino group should appear ih the 'p' rither than in the a-position therepi. ,Thusit found that whereas p-naph hylfa give a high yield of a quinazolone. ocamineis nonreactive.

has b ear pht Suitable aromatic amines are aniline, p-toluidine, p-anisidine,ap -1 hr;netidine, 'o-nitro-aniline, m-nitraniline, p-nitra iilfir e, pchloroaniline, ,B-naphthylamine, phenyl hydrazinc and the like. Benzylamine and menaphthyla 1 amine are representative examples of the aralkyl amines...-- V. v

"The $61 "ents used'shouldlbe iner.t;to..the..react ants and should be'norin'ally 'liduidj As solvents there may be employed normally liquid aromatic hydrocarbons such as benzene, toluene and the like, the chlor derivatives thereof, such as monochlor benzene, monochlor toluene and the like, normally liquid aliphatic hydrocarbons such as octane, solvent naphtha, kerosene, and their chloro derivatives such as ethylene chloride, butyl chloride and chlorkerosene,and normally liquid nitrogenous heterocyclic bases such as pyridine, quinoline and the like.

The reaction by which the substituted quinazolones are produced, assuming that the N- acyl-o-amino carboxylic acid, is N-acetyl anthranilic acid, and that the primary amine is aniline, may be graphically represented as follows: I

+ B31 03 snol sri'to It will be seen that according to this reaction 3 mols of the N-acetyl' anthranilic acid and 3 mols of aniline are used for each mol of phosphorus trichloride. It is airinteresting fact that although the amount of V phosphorus trichloride employed can combinewith only half the water formed, all of the Water is nevertheless removed. Proceeding from this observation, attempts were made to] increase the yield of the substituted quinazolone byincreasing the quantitypf phos phorus trichloride used, on the theory that greater amounts of phosphorus trichloride would facilitate removal of water and increase the 4 of a mol of the phosphorus chloride for each mol of the N-acyl-o-amino carboxylic acid may be used while obtaining good results, but the reaction becomes progressively more sluggish and the yields proportionately smaller. If the phosphorus ,chloride be eliminated entirely, no reaction takes place, from"which it; will be appreciated that the phosphorus trichloride or phosphorus oxychloride in the amounts given is a prerequisite to the successful conversion of the reactants- -into the substituted quinazolones. -The acylami-no carboxylic acids and the ines arefusediin 'i'nolar proportions, by which roughly for each mol of the acylmino parboxylicgacid there will be employed 1 mp1 of the amine.

.' 'f' iThe'substituted 'quinazolones of the present invention may be utilized as intermediates in the formation of dyestuffs.

The following examples serve to further illustrate the invention but it is to be understood that theselexam'pleslare. illustrative, and not limitative in nature. The parts'are by weigh t.

' Example I..-2-methyl-S-p-chlorophenyZ-L" quinazolon'e 12.75 parts of 'pchloroaniline, 17.9 parts of fN-acetyl anthranilic acid and 160 parts of toluene are agitated and slowly treateddropwise with 4.6 parts ofphosph'orus trichloride in '20 parts of toluene. A white suspensionforms and remains throughout thereaction The mixture is heatedto the reflux temperature and agitated for 1 to 2 hours., After treating with 200p'arts 'of1 1 0%' sodium carbonate solution," the toluene is removed by steam distillation. The white solid is removed by filtration, washed with Water and .dried. .There are obtained 21.6 parts of crude product melting at 155 to 158C. This represents of the theoretical yield, After recrystallization from alcohol, the, melting point was foundto be15f? to 158 C.

Analysis:

l. Galcd. Found 0. 66.5 I 66.74 H. 4.10 414 N; 1 .3 10.52

"EA 'benz'o" substituted 2-methy1-3-p-chlorophnyls-A-quihazolone was obtained .Whilecoperatirig. as above but While using N-acetyl-oeamino naphtho'ic acid in place of.:the N-acetyl. anthranilic acid; iThisfproduct ha's the following for- .ici

and is 2 methyl ?.rp chloro-phenyl-6,7-benzoquinazolone.

Example II.2-methyl 3-ZauryZ-4-quinazoione Calcd. Found Example III .2 -methyl- 3 -phenyl- 6 -chl oro- 4 quinazolone 19.2 parts of N-acetyl-5-chloroanthranilic acid, 8.4 parts of aniline and 140 parts of toluene are agitated and slowly treated dropwise with 4.2 parts of phosphorus trichloride in 20parts of toluene. The suspension is well stirred, heated to reflux and maintained at the reflux temperature for 1 to 2 hours. carbonate the toluene is removed by steam distillation. The solids formed are removed by filtration, washed with water and dried. There result 14.9 parts (61% of theory) of crude product melting at 173 to 177 C. After recrystallization from alcohol, the 2-methyl-3-phenyl-6-chloro-4- quinazolone melts at 181 to 182 C.

Analysis:

Oalcd. Found Example IV.--2-methyl-3-anilin0-4-quinaeo lone 17.9 parts of N-acetylanthranilic acid, 10.8 parts of phenylhydrazine and 140 parts of toluene are agitated and slowly treated with a solution of 4.6 parts of phosphorus trichloride in 20 parts of toluene. The resulting suspension is stirred, heated to the reflux temperature and maintained at this temperature for 1 to 2 hours. After adding 200 parts of sodium carbonate, the toluene is removed by steam distillation. The solid remaining in the boiler is removed by filtration, washed with water and dried. There is obtained 15.8 parts of pure 2-methyl-3-anilino-4- quinazolone melting at 207 to 209 C. This represents a yield equivalent to 63% of the theoretical,

Example V.2-methyl-3-!o -nitro-phenyl-4-quinazolone The procedure is the same as in Example I excepting that there are used 13.8 parts of a-nitroaniline in lieu of the p-chloro-aniline.

Various modifications of our invention will occur to persons skilled in the art and we therefore do not intend to be limited in the patent granted except as required by the prior art and the appended claims.

We claim:

1. The process of preparing substituted -quinazolones which comprises heating an N-acyl-oamino cyclic carboxylic acid selected from the class consisting of aromatic and heterocyclic carboxylic acids with a primary amine selected from the class consisting of primary aliphatic, aro- 6 matic and araliphatic amines, the aromatic amine when containing a condensed ring system hearing the amino group in the fi-position thereof, in the presence of a phosphorus chloride selected from the class consisting of phosphorus trichloride and phosphorus oxychloride.

2. The process of preparing substituted i-quinazolones which comprises heating a mixture of an N-acyl-o-amino-cyclic carboxylic acid selected from the class consisting of aromatic and heterocyclic carboxylic acids with a primary amine selected from the class consisting of primary ali- After adding 200 parts of 10% sodium phatic, aromatic and araliphatic amines, the arcmatic amine when containing a condensed ring system bearing the amino group in the p-position thereof, in the presence of a phosphorus chloride selected from the class consisting of phosphorus trichloride and phosphorus oxychloride and a normally liquid inert organic solvent.

3. The process as defined in claim 2 wherein said solvent is an aromatic hydrocarbon.

4. The process as defined in claim 2 wherein the reactants are heated to the refluxing temperature of the solvent.

5. The process as defined in claim 2 wherein the inert solvent is toluene and wherein the reactants are heated to the refluxing temperature of the solvent.

6. The process as defined in claim 1 wherein the N-acyl-o-amino-cyclic carboxylic acid is of the benzene series and the primary amine is aliphatic.

7. The process as defined in claim 1 wherein the N-acyl-o-amino-cyclic carboxylic acid is of the benzene series and the primary amine is aromatic.

8. The process as defined; in claim 1 wherein for each mol of the N-acyl-o-amino-carboxylic acid and of the primary amine there is used of a mol of said phosphorus chloride.

9. The process of preparing 2-methyl-3-phenyl- 6-chloro-4-quinazolone which comprises refluxing N-acetyl-S-chloro anthranilic acid and aniline in toluene in the presence of phosphorus trichloride.

10. The process of preparing 2-methyl-3- lauryll-quinazolone by refluxing N-acetyi anthranilic acid and lauryl amine in toluene in the presence of phosphorus trichloride.

11. The process of preparing 2-methyl-3-anilino-4-quinazolone which comprises refluxing N- acetyl anthranilic acid and phenyl hydrazine in toluene in the presence of phosphorus trichloride.

ALFRED GUE'NTHER. JACK F. MORGAN.

REFERENCES CITED The following references are of record in the flle of this patent:

UNITED STATES PATENTS Number Name Date 2,089,971 Lesser Aug. 1'7, 193'? 2,090,603 Winkelmuller Aug. 17, 1937 OTHER REFERENCES Jour. fiir Praktische Chemi (2), vol. 36; page 165.

Jour. Am. Chemical Society, vol. 34, pages 199, 527, 519. 

